7. Abstract Metabolic bone diseases including osteoporosis (OP), osteopenia, osteomalacia and renal osteodystrophy (ROD) affect more than 55 million Americans with an annual cost of more than $17B. The gold standard, dual energy X-ray absorptiometry (DEXA) measures bone mineral density (BMD). However, the majority of bone, the organic matrix and water which together occupy ~60% of bone by volume, is inaccessible. A recent study of over 14,613 participants found that ~80% of all non-vertebral fractures occurred among individuals with BMD above the WHO definition of OP. Furthermore, the etiologies and treatments for OP/osteopenia (reduced bone content) and osteomalacia/ROD (reduced mineralization) are different, but DEXA cannot differentiate between these diseases. More comprehensive techniques are needed for the evaluation of cortical and trabecular bone quantity/quality with information not only about mineral, but about organic matrix and water. Bone is ?invisible? with clinical MRI sequences due to its short T2*. Ultrashort echo time (UTE) sequences with minimal TEs of 8 s make it possible to detect signal from bone. In the first four years of this award (1R01 AR068987, 09/2015 ? 08/2019), we investigated 3D UTE Cones imaging of bound and pore water content as well as T1, T2* and magnetization transfer (MT) ratio. However, those biomarkers showed only low to moderate correlation with biomechanics, likely due to inaccurate measure of bound and pore water as well as incomplete assessment of organic matrix and mineral in bone. UTE with a soft-hard composite pulse suppresses chemical shift artifact, thus allowing more accurate measure of total water. Double adiabatic inversion recovery UTE (DIR-UTE) provides more complete suppression of pore water, thus allowing more accurate measure of bound water. UTE with MT (UTE-MT) modeling measures collagen proton fraction, exchange and relaxation. UTE with quantitative susceptibility mapping (UTE-QSM) maps bone susceptibility, providing information about BMD. Our goal is to develop a package for fast and accurate mapping of total, bound and pore water, collagen proton fraction, exchange, relaxation, and mineral, and to apply it to OP, osteopenia and ROD patients. Aim 1 targets UTE techniques for fast and accurate mapping of water, collagen and mineral in femur (midshaft, head and neck), using CT, histomorphometry, Raman and gravimetry as reference standard. Aim 2 will evaluate UTE techniques for water, collagen and mineral in femur from donors with OP (n=20), osteopenia (n=20) and ROD (n=20), with UTE biomarkers correlated with CT, histomorphometry, Raman and biomechanical testing. Aim 3 targets translational UTE sequences to measure water, collagen and mineral in femur of young (<40y, n=30) and older women (>70y) with (n=30) and without (n=30) OP, with osteopenia (n=30) and with ROD (n=30). UTE biomarkers in different groups will be compared, and correlated with BMD, biochemical markers and fracture history. This work will provide panels of 3D UTE biomarkers for more accurate assessment of bone quantity and quality, and may have a major impact on the diagnosis of various metabolic bone diseases.